Metabolic syndrome-diabetes represents a cluster of high risks for atherothrombosis (obesity, dyslipidemia, hypertension, insulin resistance) and is characterized by chronic and systemic inflammation that evolves eventually to atherosclerosis and thrombosis. A hallmark early event for the disease is endothelial injury that expresses and releases adhesion molecules, among them von Willebrand factor (VWF). VWF is the most widely used marker for endothelial injury, but much less studied for its adhesive properties and roles in the initiating and propagating atherothrombosis. This is despite the findings that mice deficient in VWF develop less atherosclerotic lesions. We have recently found that the activity of ADAMTS-13, which cleaves ULVWF to reduce its adhesiveness, is decreased in patients with severe systemic inflammation. The decrease is also observed in mice with hypercholesterolemia. We further find that ADAMTS-13 synthesis is severely reduced in the liver of diabetic mice. These preliminary results and published data have led us to hypothesize that ULVWF proteolysis is deficient or insufficient in metabolic syndrome due to persistent ULVWF release by inflamed endothelial cells and inhibition of ADAMTS-13 synthesis and activity. As a result, un- or partially cleaved ULVWF on endothelial cells tether and aggregate platelets and leukocytes that promotes endothelial injury and atherothrombosis. We proposed to test this hypothesis by clinical, animal, and in vitro studies to answer four specific questions. First, is ULVWF proteolysis deficient in metabolic syndrome as measure by ADAMTS-13 activity and the adhesive properties of plasma VWF? Second, does the deficiency correlate with the initiation and propagation of atherosclerotic lesions? Third, what causes the deficiency? We will specifically focus on the effects of inflammatory adipokines, soluble VWF, lipids, glucose, and insulin on ADAMTS-13 synthesis and activity. Fourth, can recombinant ADAMTS-13 reduce or delay the vascular injury and atherosclerotic lesions? For this, we will periodically administer recombinant ADAMTS-13 to mice that suffer obesity, hypercholesterolemia, and diabetes. The proposed studies will help us to understand the pathophysiology of metabolic syndrome-diabetes and its common atherothrombostic complications (and systemic inflammation). They will also provide new therapeutic target to treat and prevent the disease. PROJECT NARRATIVE: This is project is designed to study how proteolysis of ULVWF becomes deficient in conditions of metabolic syndrome-diabetes. It will investigate pathophysiological changes in ADAMTS-13 synthesis and activity in patients with metabolic syndrome- diabetes, in mice bearing components of this syndrome, and in a set of in vitro experiments. Results of the study will help us to understand how defective ULVWF proteolysis contributes to the development of atherothrombosis associated with the syndrome.